The proposal is to continue research into the mechanisms of anaphylactic type reaction in man. The basic approach is immunologic and the major tool is an in vitro model: the antigenically induced release of histamine from isolated human leukocytes. A basic tenet of the approach is that the in vitro anaphylactic reaction is an active, multistep response of a viable cell which is similar to a secretory process. This in vitro system has been shown to reflect the clinical situation. Utilizing this system we will be devoted to the study of modified antigens whose allergenic potential has been decreased while their immunogenic abilities have been largely maintained. The nature of the immunoglobulins on the cell which mediate histamine release will be studied in collaboration with the Ishizakas. The intracellular events triggered by the antigen-antibody union will be studied with cells in different stages of the reaction. A number of inhibitors will be used in an attempt to understand the nature of these various stages. We will also continue to study the antibodies which can block allergic in vitro histamine release, both those found in the serum and those in the external secretions. Clinical correlations will be at the level of understanding changes in "blocking" and reaginic antibody levels and alterations in cellular reactivity brought about by immunotherapy, although the major part of this correlation is the subject of another grant. The system will also be used as a screening device for pharmacologic agents which might have clinical use.